2{40 -hydroxy-2,3,5-trimethyl-6,7-benzomorphan

ABSTRACT

Novel 2,3,5-trisubstituted-2&#39;&#39;-hydroxy-6,7-benzomorphan compounds, their methods of preparation and their use as effective analgesic agents is described.

United States Patent Robinson et al. Oct. 24, 1972 [541 2'-HYDROXY-2,3,S-TRIMETHYL-6,7- 3,345,575 16/196? Gordilll'lf....IJQL280/010. 1'3

BENZOMORPHAN 3,351,626 1 1/1967 Bartel-Keith et al.260/DIG. 13 V Inven s: M. Robinson, Ambler; Paul Al'cl lel' 260/D]G- s Anderson, Lansdale of Pa. 3,5 Robinson et 3,513,169 5/1970 Robinson et a1. 260/D1G. 13 [73] Assignee: Merck 8: Co., Inc., Rahway, NJ. R PUBL CATION v [22] Filed: 1969 J Med Ch 0 1 N L (1965) s 235 2 8 em.,vo. 8, 0. ,pp. 3 [21] Appl. No.. 793,571 chignen et aL [52] US. Cl ..260/293.54, 424/267, 260/DIG. 13 Primary Examiner-Henry R. Jiles [51] Int. Cl. ..C07d 39/00 Assistant Examiner-S. D. Winters [58] Field of Search ....260/294.7 B, 293.54, DIG. 13 Attorney-Michael C. Sudol, Jr., Harry E. Westlake,

Jr. and I. Louis Wolk 1 [5 6] References Cited 7] ABSTRACT UNITED STATES PATENTS Novel 2 ,3 ,5-tnsubst1tuted-2-hydroxy-6,7-benzoiiajzberg et morphan compounds, their methods of preparation ay ff l ms is described 3,250,678 5/1966 Archer ..260/DIG. 13 and use 386 we ana gem age 3,320,265 5/ 1967 Clarke ..260/DIG 13 1 Claim, No

SUMMARY OF THE INVENTION This invention relates to new benzomorphan derivatives, the processes for preparing the same and their method of treatment as medicinal agents. The disclosed class of compounds in this invention has pronounced analgesic activity that is effective in the relief of pain.

BACKGROUND OF THE INVENTION The most widely used drug to combat pain is still morphine. There are severe effects of this drug, however, for prolonged use of morphine generally leads to physiological and psychological dependency on the drug. In addition, it has a depressing effect on respira tion. A tireless and expensive search for an analgesic that would be as potent as morphine, but free of its dangerous effects, has been carried on. Many analgesic disclosures related to the morphine model have been synthesized, the best known of which is pethidine. This was originally thought to be a non-addicting drug, but was soon found to have dangerous addiction liability. Other synthetic analgesics include a group of substances called benzomorphans. The best known member of this group is phenazocine, but morphine, this is also dangerously addicting.

DESCRIPTION AND PREFERRED EMBODIMENTS This invention relates to a new group of chemical compounds which are 2,3,5,-trisubstituted-2'-hydroxy- 6,7-benzomorphans and relates further to the non-toxic pharmaceutically acceptable salts thereof. This invention further relates to the novel methods of preparation of the instant 2,3,5,-trisubstituted-2'-hydroxy-6,7- benzomorphans.

The compounds of this invention can be represented by the following structure:

wherein R is hydrogen, CN, COR or -CH R where R is hydrogen, alkyl (preferably lower alkyl such as methyl, ethyl, propyl, isopropyl, etc.), alkenyl (preferably loweralkenyl such as vinyl, isopropenyl, allyl, methallyl, 3-butenyl, etc.), cycloalkyl (preferably cycloloweralkyl such as cyclopropyl, cyclobutyl, etc.), cycloalkyl alkyl (preferably cycloloweralkyl lower alkyl such as cyclopropylmethyl, cyclopropylethyl, etc.), cycloalkenyl (preferably cyclolowerlakenyl such as l-cyclobutenyl, 2-cyclobutenyl, 3-cyclopentenyl, etc.), cycloalkenylalkyl (preferably cycloloweralkenyl lower alkyl such as l-cyclobutenylmethyl, 2- cyclobutenylmethyl, etc.), alkylcycloakyl (preferably loweralkylcycloloweralkyl such as methyl cyclopropyl, ethylcyclopropyl, etc.), alkenylcycloalkyl (preferably loweralkenylcycloloweralkyl such as methylenecyclopropyl, methylenecyclobutyl, 3-vinylcyclopentyl, etc.), a]- kylcycloalkenyl (preferably lower alkylcycloloweralkenyl such as 2,2,3-tn'methylcyclopenyl, Z-methylcyclopentyl, etc.), spiroalkyl (preferably spiroloweralkyl such as spiropentyl, 5-spiro-(3,2)-hexyl);

R is alkyl (preferably loweralkyl such as methyl,

ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, tbutyl, etc.), cycloalkyl, aryl (preferably phenyl or a substituted phenyl that is capable of forming an aryl lithium reagent such as p-methoxyphe'nyl), aralkyl (preferably arloweralkyl such as benzyl, phenethyl, etc. and

R is alkyl (preferably loweralkyl such as methyl,

ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, tbutyl, pentyl, etc.), aryl (preferably phenyl), and substituted .aryl (preferably substituted phenyl, provided the substituent will not react with a lithium reagent such as p-methoxyphenyl).

Included in invention are the geometric isomers of the above-noted structure in which the two substituents R and R are either in cis or trans-relationship to each other. 7

Either isomer discussed above can further be separated into its optical isomers [dextro and levo by preparing the diastereoisomeric salts with optically active acids either d or I which salts then can be separated by conventional methods such as fractional crystallization. Thus, it is to be understood that included in this invention, along with the novel 2,3,5- trisubstituted-Z-hydroxy-6,7-benzomorphan derivatives, are the individual optical isomers, that is the dextrorotatory as well as the levorotatory isomers of our novel benzomorphan compounds.

The more preferred aspects of this invention relate to the benzomorphans and the salts thereof of the following formula:

wherein R is hydrogen or -CH R where R is hydrogen, lower alkyl (such as methyl or ethyl) cycloloweralkyl (such as cyclopropyl) or loweralkenylcycloloweralkyl (such as methylenecyclopropyl); R is lower alkyl (such as methyl or ethyl); and, R is lower alkyl (such as methyl, ethyl, propyl or butyl). Representative compounds of :this invention are as follows:

3,5-dimethyl-2'-hydroxy-6,7-benzomorphan; 3-ethyl-5-methyl-2-hydroxy-6,7-benzomorphan; 3-methyl-5-n-propyl-2'-hydroxy-6,7-benzomorphan; 3-methyl-5-n-butyl-2-hydroxy-6,7-benzomorphan; 2,3,5-trimethyl-2-hydroxy-6,7-benzomorphan; 2,3 ,5-trimethyl-2'-hydroxy-6,7-benzomorphan; 2,5-dimethyl-3-ethyl-2'-hydroxy-6,7-benzomorphan;

2,5-dimethyl-3-n-propyl-Z'-hydroxy-6,7-

benzomorphan;

2,5-dimethyl-3-i-propyl-2'-hydroxy-6,7-

benzomorphan;

2-ethyl-3,5 -dimethyl-2-hydroxy-6,7-

, benzomorphan;

2-propyl-3,5-dimethyl-2'-hydroxy-6,7-

benzomorphan;

3 2-cyclopropylmethyl-3-ethyl-5-methyl-2-hydroxy- 6,7-benzomorphan; 2,3-dimethyl--n-propyl-2'-hydroxy-6,7-

benzomorphan; 2 ,3-dimethyl-5-n-butyl-2 '-hydroxy-6,7-

benzomorphan; 2-cyclopropylmethyl-3-methyl-5-n-propyl-2- hydroxy-6,7-benzomorphan; 2-methyl-3-ethyl-5-n-propyl-2'-hydroxy-6,7- benzomorphan; 2-methyl-3-ethyl-5-n-butyl-2'-hydroxy-6,7-

benzomorphan; 2,3-dimethyl-5-pentyl-2'-hydroxy-6,7-

benzomorphan; Z-methylenecyclopropylmethyl-S-methyl-S-npropyl-2'-hydroxy-6,7-benzomorphan; 2-cyclopropylmethyl-3-methyl-5-n-butyl-2'-hydroxy-6,7-benzomorphan; 2-methylenecyclopropylmethyb3-methyl-5-n-butyl- 2-hydroxy-6,7-benzomorphan; 3,5-dimethyl-2-(2-methylenecyclopropylmethyl)-2'- hydroxy-6,7-benzomorphan; 3,5-dimethyl-2-(2-methylenecyclopropylmethyl)-2'-hydroxy-6,7-benzomorphan; 2-(3-cyclopenten-1-yl methyl)-2-hydroxy-3,5-

dimethyl-6,7-benzomorphan HCl; A further aspect of this invention embraces a method of treatment of the relief of pain by the administration of compounds having the structural formula:

wherein R is hydrogen, CN, COR, or Cl-l R where R is hydrogen, alkyl (preferably lower alkyl such as methyl, ethyl, propyl, isopropyl, etc.), alkenyl (preferably loweralkenyl such as vinyl, isopropenyl, allyl, methallyl, 3-butenyl, etc.), cycloalkyl (preferably cycloloweralkyl such as cyclopropyl, cyclobutyl, etc.), cycloalkyl alkyl (preferably cycloloweralkyl lower alkyl such as cyclopropylmethyl, cyclopropylethyl, etc.), cycloalkenyl (preferably cycloloweralkenyl such as l-cyclobutenyl, 2-cyclobutenyl, 3-cyclopentenyl, etc.), cycloalkenylalkyl (preferably cycloloweralkenyl lower alkyl such as l-cyclobutenymethyl, 2- cyclobutenylmethyl, etc.), alkylcycloalkyl (preferably loweralkylcycloloweralkyl such as methyl cyclopropyl, ethylcyclopropyl, etc.), alkenylcycloalkyl (preferably loweralkenylcycloloweralkyl such as methylenecyclopropyl, methylenecyclobutyl, 3-vinylcyclopentyl, etc.), alkylcycloalkenyl (preferably lower alkylcycloloweralkenyl such as 2,2,3-trimethylcyclopropenyl, Z-methylcyclopentyl, etc.), spiroalkyl (preferably spiroloweralkyl such as spiropentyl, 5-spiro -(3,2-hexyl R is alkyl (preferably loweralkyl such as methyl,

ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, tbutyl, etc.), cyclo alkyl, aryl (preferably phenyl or a substituted phenyl that is capable of forming an aryl lithium reagent such as p-methoxypehnyl), aralkyl (preferably arloweralkyl such as benzyl, phenethyl, etc.); and

R5 is alkyl (preferably loweralkyl such as methyl,

4 ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, tbutyl, pentyl, etc.), aryl (preferably phenyl), and

substituted aryl (preferably provided the substituent will not react with a lithium reagent such as p-methoxyphe'nyl).

Included in this invention is the method of treatment of the relief of pain by the administration of compounds of the above structure and their optical isomers.

The more preferred aspects of this invention embraces a method of treatment of the relief of pain by the administration of compounds having the structural The lack of narcotic antagonist activity can be advantageous because of the observation that high antagonist activity has generally been associated with undesirable side effects.

' A further feature of this invention resides in the fact that the compounds of this invention can be produced by synthetic means more conveniently than are members of the morphine familyof naturally occurring alkaloidal analgesics.

The compounds of this invention are administered orally or subcutaneously, preferably as an aqueous solution of the hydrochloride salt and in the range of about 0.110 mg./kg. to about 18 mgJkg. per day.

Various tests in animals have'been carried out to show the ability of the compounds of this invention to exhibit reactions that can be correlated with activity in humans. One such test as outlined by Charles A. Winter and Lars Flataker in The Journal of Pharmacology and Experimental Therapeutics, Volume 150, No. 1, pages 165-171, shows the ability of the instant compounds to exhibit analgesic effect. Measurements are made of the reaction threshold to pressure in the hind paws of rats injected with a phlogistic agent. These are compared with known analgesic drugs and marked increased efl'ects can be found. Drug dosages of upto 18 mg./kg. are administered by the subcutaneous route. The experiments are carried out on Sprague- Dawley female rats weighing from 60 to grams. The response threshold is determined by applying pressure to the foot and reading on a manometer the pressure at i which an audible squeak is elicited. Groups of three to six rate are used for each test and the average reading is recorded.

The activity of the instant compounds when tested by the procedure of Winter et al. as outlined above in- 6 IOCH:

\NC H3 1H H O 2 j C a A B3 I N H3 11!! VIII Ra Ra temperature may be raised (preferably reflux) to give the dihydropyridine derivative V. Reduction of this dihydropyridine derivative V is then carried out in an aqueous or alcoholic medium (preferably in aqueous methanol) at a lower temperature (preferably between and 35C.) with sodium borohydride. The tetrahydro compound VIII results. Treatment of this intermediate with hot 48 percent hydrobromic acid (reflux being most convenient) gives the instant 2- methyl-3,S-disubstituted-Z-hydroxy-6,7- benzomorphan Ill.

The 2-methyl-3,5-disubstituted-2-hydroxy-6,7- benzomorphan III may also be prepared by sodium borohydride reduction of the 2,4-disubstituted-lmethylpyridium halide IV to the 2,4-disubstituted-lmethyl-l,2,3,6-tetrahydropyridine VI, which is converted to the p-methoxybenzyl chloride quaternary VII. The quaternary salt VII is then rearranged with phenyl lithium in the Stephens rearrangement in an invert solvent (such as ether) to give 6-p-rnethoxybenzyl-lmethyl-2 ,4-disubstitute d- 1 ,2,3,6-tetrahydropyridine VIII. This is then cyclized with 48 percent hydrobromic acid to the desired 2-methyl-3,5-disubstituted-2'- hydroxy-6,7-benzomorphan III.

The following equations illustrate the methods of preparation:

I N N-CH: R RI! RaRr 9 R E: NCH l i R R3 OCH l a z l Xe e N-CH; R Ra +152 VII Mg CoHgLi C1 wherein R, R and R are as described above, and X is halide (preferably bromide oriodide).

The preparation of a 3,5-disubstituted-2'-hydroxy- 6,7-benzomorphan II is preferably carried out by acylating the 3,5-disubstituted-2'-hydroxy-2-methyl- 6,7-benzomorphan III at the 2'-position with acetic anhydride, heating the acylated compound at elevated temperature with cyanogen bromide in an organic solvent, preferably a halogenated hydrocarbon such as chloroform, thereby replacing the Z-methyl group with a cyano group and then removing the cyano and acetyl groups by hydrolysis in a dilute acid solution.

The 2,3,5-trisubstituted-2'-hydroxy-6,7- benzomorphans I of this invention can be prepared by the following process. The reaction of 3,5-disubstituted-Z'-hydroxy-6,7-benzomorphan with two equivalents of an acid halide of the formula RCOX (wherein X is chloride or bromide, and R is as defined above for Structure I, in an inert solvent such as chloroform or benzene) and preferably in the presence of a tertiary amine base (such as pyridine or triethylamine) to form the corresponding 3,5-disubstituted-Z'-acyloxy-2-acyl-6,7-benzomorphan derivative 0 l [3, 5-disubstltuted-2'-(0CR)2( R)-6, 7-benzomorphan wherein R is as defined above]. Reduction of these derivatives, for instance with lithium aluminum hydride in diethyl ether or tetrahydrofuran, gives the 2,3,5- trisubstituted-2-hydroxy-6,7-benzomorphan compounds of this invention.

In the above process, the desired end products are isolated from their particular reaction solutions or mixtures by methods known in the art.

The 2,3,5-trisubstituted-2-hydroxy-6,7- benzomorphans of this invention can be used as such or in the form of their non-toxic pharmaceutically acceptable acid-addition salts. Suchsalts are prepared from suitable acids (such as inorganic acids as hydrochloric or sulfuric acid or organic acids such as acetic or maleic acid and the like). The acid-addition salts are prepared by reacting the appropriate benzomorphan base with approximately one equivalent of the suitable acid in an organic solvent (such as diethyl either or alcohol) or aqueous solution.

' throughout the literature.

The isomeric forms of 3,5-disubstituted-2-hydroxy- 6,7-benzomorphan II may also be employed in the preparation of compounds of Structure I. These isomeric compounds may be prepared by known methods, using a resolving agent such as carnphor sulfonic acid, tartaric acid, dibenzoyl tartaric acid and the like to form the levo and dextro isomers. Each optical isomer of 3,5-disubstituted-2-hydroxy-6,7- benzomorphan can then be used as the starting material in the various examples resulting in dextro or levo 2,3,5-trisubstituted-2'-hydroxy-6,7- benzomorphans. Alternatively, the racemic 2,3,5- trisubstituted-Z'-hydroxy-6,7-benzomorphan end products can themselves be resolved according to a procedure similar to that described above to yield the dextrorotatory and levorotatory isomers of 2,3,5-tn'substituted-2-hydroxy-6,7-benzomorphans.

The following examples illustrate the various methods described above for the preparation of the novel 2,3,5-trisubstituted-2-hydroxy-6,7- benzomorphans of the present invention.

The Examples should be construed as illustrations of the invention and not as limitations thereof.

EXAMPLE 1 EXAMPLE la l,2-Dimethyl-4-n-butylpyridine iodide 4-N-butyl-pyridine To a stirred slurry of 40 g. of sodium arnide in 650 ml. of liquid ammonia is added at a fast drip 93 grams (1 mole) of gamma-picoline. Stirring is continued 20 minutes and then 78.5 g. (1 mole) of l-chloropropane is added at such a rate as to maintain gentle refluxing. The ammonia is allowed to evaporate and the residue treated with 200 ml. of water. The aqueous mixture is extracted three times with 200 ml. of ether. The combined extracts are dried over MgS filtered and the filtrate concentrated under vacuum. Distillation gives 83 grams of 4-butylpyridine, b.p. 110l13/35mm. 2-Methyl-4-n-butylpyridine To a stirred solution of 1 mole of methyllithium in 300 ml. of ether and 500 ml. of hexane is added at a fast drip 135 grams (1 mole) of 4-n-butylpyridine dissolved in 100 ml. of hexane. The ether is removed bydistillation and the hexane solution is then heated under reflux for 8 hours. The cooled reaction mixture is poured onto ice and the organic layer separated, dried over MgS0 filtered and the filtrate concentrated under reduced pressure. Distillation through a 20 inch Vigreaux column gives 52 grams of 2-methyl-4-n-butylpyridine, b.p., 136/93 mm. 1 ,2-Dimethyl-4-n-butylpyridinium iodide A solution of 30.2g (0.202 moles) of 2-methyl-4-nbutylpyridine and 32 grams of methyl iodide (10 percent excess) in 150 ml. of acetone is cooled in an ice bath for several hours until crystallization of the methiodide appears to be complete. The crystalls are collected by suction filtration washed with a little cold acetone and then recrystallized from hot acetone to yield 46 grams of 1,2-dimethyl-4-n-butylpyridinium iodide,m.p., l13.5114.5C.

EXAMPLE lb 1,2-Dimethyl-4-n-propylpyridinium iodide 2-Methyl-4-n-propylpyridine To a stirred solution of 1 mole of methyllithium in 500 ml. of ether is added at a fast drip a solution of 121 grams (1 mole) of 4-propylpyridine in ml. of ether. The ether is removed by distillation with simultaneous addition of benzene. The resulting benzene solution is stirred and heated under reflux for Shours. The cooled reaction mixture is poured onto ice and the organic layer separated and dried over MgS0 The drying is separated by filtration and the filtrate concentrated under reduced pressure. Distillation of the concentrate gives 71 grams of 2-methyl-4-n-propylpyridine, b.p. l26--127/ 100 mm. 1,2-DimethylA-n-propylpyridinium iodide An acetone (200 ml.) solution of 2-methyl-4-n-propylpyridine (67.5 g., 0.5 moles) and methyliodide (85 g., 0.05 moles) is-heated under reflux for 2 hours and then colled in an ice bath until crystallization occurs. The salt is collected by suction filtration and recrystallized from acetone to yield 138 grams of methiodide, m.p. 8486.

EXAMPLE 2 tetrahydropyridines (b.p. l05-118/125 mm.) This is then dissolved in ml. of acetone and treated with 25 grams of p-methoxybenzyl chloride. The solution is allowed to stand, and the crystalline mass which separates is collected by suction filtration and washed with acetone to yield 37.5 g. of 1.4-dimethyl-2-ethyl-1- (p-methoxybenzyD-1,2,3',6-tetrahydropyridinium chloride.

EXAMPLE 2a 1,2-Dimethyl-4-n-butyl-1-(p-methoxybenzyl)-1,2,3,6- tetrahydropyridinium chloride 1,2-Dimethyl-4-n-butyl-1,2,3,6-tetrahydropyridine To a stirred ice cold solution of' 35.4 grams (.122 moles) of 1,2-dimethyl-4-n-butyl-pyridinium iodide in 200 ml. of 50 percent aqueous methanol is added dropwise a solution of 6g of sodium borohydride in 75 ml. of water. The solution is allowed to stirr overnight. The ethane! i rsm e by il atiq antle r d pressure and the residue is diluted with 200 ml. oft-1' 6 and extracted four times with 100 ml. portions of ether. The combined extracts are dried over MgSO filtered and the filtrate concentrated under reduced pressure. Distillation of the concentrate gives 13.1 grams of 1,2- dimethyl-4-n-butyl 1,2,3,6-tetrahydropyridine, b.p. 910 4 7/B%10 mm. v l,2-Dimethyl-4-n-butyl-l-(p methoxybenzyl)-1,2,3,6- tetrahydropyridinium chloride A solution of 14 grams (.08 moles) of 1,2-dimethyl- 4-n-butyl-1,2,3,6-tetrahydropyridine and 12.9 grams (0.08 moles) of p-methoxybenzylchloride in 150 ml. of acetone is heated under reflux for 3 hours, cooled and evaporated under reduced pressure to obtain 1,2- dimethyl-4-n-butyl-l-(p-methoxybenzyl)-l,2,3,6- tetrahydropyridinium chloride.

EXAMPLE 2b 1,2-Dimethyl-4-n-propyl-l-(p-methoxybenzyl)- 1 ,2,3,6-tetra-hydropyiidinium chloride 1,2-dimethyl-4-n-propyll,2,3,6-tetrahydropyridine A solution of grams of NaBh in 100 ml. of 0.01

molar NaOH is added dropwise to a stirred ice cold solution of 76 grams (0.5 moles) of 1,2-dimethyl-4-npropylpyridinium iodide in 400 ml. of 50 percent aqueous methanol. The solution is stirred overnight. The methanol is removed under reduced pressure and the residue is diluted with 200 ml. of 15 percent aqueous K C0 and extracted three times with 200 ml. portions of ether. The combined extracts are dried over anhydrous MgS0 filtered and the filtrate concentrated under reduced pressure. Distillation gives 26 grams of 1 ,2-dimethyl-4-n-propyll ,2 ,3,6-tetrahydropyridine b.p.132-135C./80 mm.

1,Z-Dimethyl--n-propyl-l-(p-methoxybenzyD- l,2,3,6-tetrahydropyridine A solution of 200 ml. of acetone and 30.6 grams (0.2 moles) of 1,2-dimethyl-4-n-propyl-1,2,3,6-

tetrahydropyridine and 31.2 g. (0.2 moles) of pmethoxybenzylchloride is heated under reflux for 3 hours then cooled and evaporated to dryness under reduced pressure to obtain 1,2-dimethyl-4-n-propyl-l- (p-methoxybenzyD-l,2,3,6-tetrahydropyridine.

EXAMPIEA w 1,4-Dimethyl-2-ethyl-6-(p-methoxybenzyl)-1,2,3,6- tetrahydropyridine Thirty-five grams of 1,4-dimethyl-2-ethyl-1-(pmethoxybenzyl )-1 ,2,3,6-tetrahydropyridinium chloride is slurried with 400 ml. of ether and 170 ml. of 2.07 N phenyl lithium solution is added under N as rapidly as possible. The resulting mixture is stirred for 30 minutes at room temperature and then for 3 hours under reflux. The cooled reaction mixture is poured onto ice and the organic layer is separated and extracted twice with 200 ml. portions of percent hydrochloric acid. The combined acidic extracts are made basic with ammonia and extracted three times with 200 ml. portions of ether. The combined ether extracts are dried over magnesium sulfate, filtered and concentrated under reduced pressure to yield 29 grams of oily product. Distillation of the concentrate gives 24 g. of 1,4-Dimethyl-2-ethyl-6- (p-methoxybenzyl)-1,2,3,6-tetrahydropyridine as a light yellow oil (b.p. 135140/0.06 mm.

2,3-dimethyl-5-n-butyl-2'-hydroxy-6,7-benzomorphan l0... EXAMPLE 3a 1 ,Z-Dimethyl-4-n-butyl-6-p-methoxybenzyl- 1,23,6- tetrahydropyridine To 0.03 moles of 1,2-dimethyl-4-n-butyl-123,6- tetrahydropyridine slurried in 500 ml. ofdry ether is added 137 ml. of 2.18 normal phenyllithium solution (:30 benzene-ether). ether). The reaction mixture is stirred and heated under reflux for 3 hours, cooled and poured onto ice. The organic layer is separated and extracted with aqueous hydrochloric acid. The acid extract is made basic with aqueous ammonia and extracted twice with 200 ml. portions of ether. The combined ethereal extracts are dried over MgSO filtered and concentrated under reduced pressure. The concentrate is distilled to yield 19 grams of 1,2-dimethyl-4-nbutyl-6-p-methoxybenzyl- 1 ,2 ,3,6-tetrahydropyridine, b.p l45-153C/0.4 mm.

EXAMPLE 3b 1,2-Dimethyl-4-n-propyl-6-p-methoxybenzyl-1,2,3,6- tetrahydropyridine To 0.2 moles of 1,2-dimethyl-4-n-propyl-1,2,3,6- tetrahydropyridine slurried with 500 ml. of ether is added 200 ml. of 2.18 molar phenyllithium (70:30 benzene-ether). The solution is stirred and heated under reflux for 2 hours then cooled and poured onto ice. The organic solution is separated and extracted with aqueous acid. The acidic extract is made basic with concentrated aqueous ammonia and extracted three times with 200 ml. portions of ether. The combined extracts are dried over MgSO filtered and evaporated to yield a liquid residue. Distillation of the residue gives 23 grams of 1,2-dimethyl-4-n-propyl-6-pmethoxybenzyl-l,2,3,6,-tetrahydropyridine, b.p. -135/0.1 mm.

EXAMPLE 4 2,5-Dimethyl-2'-hydroxy-3-ethyl-6,7-benzomorphan Twenty three grams of 1,4-dimethyl-2-ethyl-6-(pmethoxybenzyl)-l,2,3,6-tetrahydropyridine are dissolved in 180 ml. of 48 percent hydrobromic acid and heated at142C. for 24 hours. This solutionis then poured onto a mixture of ice and 180 ml. of concentrated aqueous ammonia and extracted with 2 X 200 ml. of chloroform. The chloroform solution is dried over magnesium sulfate, filtered and evaporated to yield a brown residue. The residue is triturated with acetone to yield 6.5 of crystalline compound. This is recrystallized from 70 ml. of hot ethanol and 3.7 g. of 2,5-dimethyl-3-ethyl-2'-hydroxy-6,7-benzomorphan, m.p. .9-201C., is collected from the ice cold ethanol solution.

A solution of 18 grams (0.63 moles) of 1,2-dimethyl-4-n-butyl-6-p-methoxybenzyl-1,23,6- tetrahydropyridine in 200 ml. of 48 percent aqueous hydrogen bromide is heated at 145C. for 24 hours, cooled and poured onto 200 g. of ice. Concentrated aqueous ammonia is added until the solution is basic. The mixture is extracted three times with 200 ml. portions of chloroform. The combined extracts are washed with water and dried over MgSO The drying agent is rat s. b ltrate an e fil t qxav r t to dryness under reduced pressure An aidriFJriToi of the residue deposits product on cooling. Recrystallization from acetone gives 2,3- dimethyl--n-butyl-2- hydroxy-6,7-benzomorphan (1.7 g) m.p. 230-23lC.

EXAMPLE 4b 2,3-dimethyl-5-n-propyl-2-hydroxy-6,7- benzomorphan A solution of 17 grams of 1,2-dimethyl-4-n-propyl-6- p-methoxy benzyl-l,2,3,6-tetrahydropyridine in 170 ml. of 48 percent aqueous hydrogen bromide is heated at 145C. for 24 hours, cooled and poured onto ice.

The solution is made basic with concentrated aqueous NH and extracted twice with 300 ml. portions of chloroform. The combined extracts are washed with water, dried over MgSO filtered and evaporated to dryness under reduced pressure. The residue is dissolved in acetone. On cooling, the acetone solution deposits 2.8 grams of product. Recrystallization from acetone gives 1.9 grams of 2,3-dimethyl-5-n-propyl-2- hydroxy-6,7,-benzomorphan, m.p. 208210C.

EXAMPLE 5 Following the procedure of Example 1 but substituting for 2-ethyl-4-methypyridine the starting materials of Table I below, there is obtained in place of 1,4- dimethyl-Z-ethylpyridinium iodide the corresponding halide salt of Table II below:

TABLE I Starting Material 2,4-dimethylpyridine 2-n-propyl-4-methyl-pyridine 2-i-propyl-4-methyl-pyridine Z-n-butylA-methyl-pyridine 2-i-butyl-4-methyl-pyridine 2-methyl-4-ethylpyridine 2-methyl-4-pentylpyridine 2,4-diethylpyridine 2-ethyl-4-n-butylpyridine 2-ethyl-4-n-propylpyridine I 2,4-dipropylpyridine 2-benzyl-4-methyl-pyridine 2-phenethyl-4-methyl-pyridine 2-methyl-4-phenyl-pyridine 2-phenyl-4-methyl-pyridine 2,4-diphenylpyridine 2-methyl-4-(p-methoxy-phenyl)-pyridine TABLE 11 Product 1 ,2,4,-trimethylpyridinium iodide l ,4-dimethyl-2-n-propylpyridinium iodide 1 ,4-dimethyl-Z-i-propylpyridinium iodide 1 ,4-dimethyl-2-n-butylpyridinium iodide l ,4-dimethyl-2-i-butylpyridinium iodide 1 ,2-dimethyl-4-ethylpyridinium iodide 1 ,2-dimethyl-4-pentylpyridiniurn iodide l-methyl-Z,4-diethylpyridinium iodide 1-methyl-2-ethyl-4-n-butyl-pyridinium iodide l-methyl-Z-ethyl-4-n-propyl-pyridinium iodide 1-methyl-2,4-dipropylpyridinium iodide 1 ,4-dimethylpyridinium iodide 1 ,4-dimethyl-2-phenethylpyridinium iodide A I-diEethyI-Z-phenylpyridinium iodide 1-methyl-2,4-diphenylpyridinium iodide 1,2-dimethyl-4-(p-methoxyphenyD-pyridinium iodide EXAMPLE6 Following the procedure of Example 2 but substituting for 1,4-dimethyl-2-ethylpyridinium iodide the halide salts of Table H, Example 5, there is obtained in place of l,4-dimethyl-2-ethyl-l-(p-methoxybenzyl)- 1,2,3,6-tetrahydropyridine chloride the corresponding l,2,4-trisubstituted-1-(p-methoxybenzyl)-l,2,3,6-

tetrahydropyridinium halide of Table I below:

TABLE I l ,2,4-trimethyll-( p-methoxybenzyl 1 ,2,3,6-

tetrahydropyridinium chloride 1,4-dimethyl-2-n-propyl-l-(p-methoxybenzyl)- l,2,3,6-tetrahydropyridinium chloride 1 ,4-dimethyl-2-i-propyll-(p-methoxybenzyl 1 ,2,3,6-tetrahydropyridinium chloride 1 ,4-dimethyl-2-n-butyl- 1 p-methoxybenzyl l,2,3,6-tetrahydropyridinium chloride 1 ,4-dimethy-2-i-butyl- 1- p-methoxybenzyl 1 ,2,3,6-

tetrahydropyridinium chloride 1 ,2-dimethyl-4-ethyl- 1-( p-methoxybenzyl )-1 ,2,3,6-

tetrahydropyridinium chloride- 1,2-dimethyl-4-pentyl-1-(p-methoxybenzyl)-1,2,3,6-

EXAMPLE 7 Following the procedure of Example 3 but substituting for 1,4-dimethyl-2-ethyl-l-(p-methoxybenzyD- 1,2,3,6-tetrahydropyridinium chloride the corresponding 1-(p-methoxybenzyl)-1,2,3,6-pyridinium halides of Table 1, Example 6, there is obtained in placed of 1,4- dimethyl-2-ethyl-6-(p-methoxybenzyl 1 ,2,3,6- tetrahydropyridine the. corresponding 1,2,4-trisubstituted-6-(pmethoxybenzyl)-1,2,3,6- tetrahydropyridinium compounds of Table I below;

TABLE I 1,2,4-trimethyl-6-(p-methoxybenzyl)-1,2,3,6-

tetrahydropyridine 1,4-dimethyl-2-n-propyl6-(p-methoxybenzyl)- 1,2,3,6-tetrahydropyridine thykkpheqylpy iniumiQdKE 1,4-dimethyl-2-i-propyl-6-( p-methoxybenzyl)- l,2,3,6-tetrahydropyridine 1,4-dimethyl-2-n-butyl-6-(p-methoxybenzyl)- 1 ,2,3,6-tetrahydropyridine l,4-dimethyl-2-i-butyl-6-(p-methoxybenzyl)-l,2,3,6- tetrahydropyridine v 1 ,2-dimethyl-4-ethyl-6-(p-methoxybenzyl)-1,2,3,6-

tetrapropyridine 1 ,2-dimethyl-4-pentyl-6-( p-methoxybenzyl)-1 ,2,3 ,6-

tetrahydropyridine methoxybenzyl )-1,2,3 ,6-tetrahydropyridine 1-methyl-2-ethyl-4-n-butyl-6-(p-methoxybenzyl l ,2,3,6-tetrahydropyridine' 1-methyl-2-ethyl-4-n-propyl-6-(p-methoxybenzyl 1,2,3,6-tetrahydropyridine 1-methyl-2,4-dipropyl-6-(p-methoxybenzyD-l,2,3,6-

tetrahydropyridine 1 ,4-dimethyl-2-benzyl-6-(p-methoxybenzyl )-1 ,2,3 ,6-

tetrahydropyridine 1 ,4-dimethyl-2-phenethyl-6-(p-methoxybenzyl)- 1,2,3 ,6-tetrahydropyridine 1,2-dimethyl-4-phenyl-6-(p-methoxybenzyl)- 1,2,3 ,fi-tetrahydropyridine 1,4-dimethyl-2-phenyl-6-(p-methoxybenzyl)- 1,2,3,6-tetrahydropyridine 1-methyl-2,4-diphenyl-6-(p-methoxybenzyl)- 1,2,3,6-tetrahydropyridine 1,2-dimethyl-4-(p-methoxyphenyl)-6-(p-methoxybenzyl)-1,2,3,6-tetrahydropyridine EXAMPLE 8 tetrahydropyridine compounds of Table 1, Example 7,

there is obtained in place of 2,5-dimethyl-3-ethyl-2'- hydroxy-6,7-benzomorphan the corresponding benzomorphans of Table I below:

TABLE I 2,3,5-trimethyl-2-hydroxy-6,7-benzomorphan 2,5-dimethyl-3-n-propyl-2'-hydroxy-6,7-

benzomorphan 2,5-dimethyl-3-i-propyl-2-hydroxy-6,7-

benzomorphan 2,5-dimethyl-3-n-butyl-2-hydroxy-6,7-

benzomorphan 2,5-dimethyl-3-i-butyl-2'-hydroxy-6,7-

benzomorphan 2,3-dimethyl--ethyl-2'-hydroxy-6,7-benzomorphan 2,3-dimethyl-5-pentyl-2'-hydroxy-6,7-

benzomorphan 2-methyl-3,S-diethyl-Z-hydroxy-6,7-benzomorphan 2-methyl-3-ethy1-5-n-propyl-2-hydroxy-6,7-

benzomorphan 2-methyl-3 -ethyl-5-n-butyl-2'-hydroxy-6,7-

benzomorphan 2-methyl-3,5-dipropyl-2-hydroxy-6,7-

benzomorphan 2,S-dimethyl-3-benzyl-2-hydroxy-6,7-

benzomorphan 2,5-dimethyl-3-phenethyl-2'-hydroxy-6,7-

benzomorphan 2,3-dimethyl-5-phenyl-2'-hydroxy-6,7-

benzoslbighaa 2,5-dimethyl-3-phenyl-2'-hydroxy-6,7-

benzomorphan 2-methyl-3,5-diphenyl-2'-hydr0xy-6,7-

benzomorphan 2,3-dimethyl'-5-(p-methoxyphenyl)-2'-hydroxy-6,7-

benzomorphan EXAMPLE 9 concentrated. The residue is taken up in 50 ml. of

chloroform and added dropwise to a solution of 3.2 g. cyanogen bromide in 30 ml. of chloroform over 1 hour with stirring. The solution is then stirred under reflux for. 3 hours and then evaporated to dryness. The residue is dissolved in 150 ml. of 6 percent hydrochloric acid and heated under reflux for 8 hours. The solution is made basic with concentrated ammonia and chloroform extracted (3 X ml.). The combined extracts are dried over magnesium sulfate, filtered and evaporated. The residue is dissolved in acetone (50 ml.), filtered and chilled for several hours. Thefiltrate deposits 2.5 grams of crystalline 3-ethyl-5-methyl-2'- hydroxy-6,7-benzomorphan, mp. 240.

EXAMPLE 10 Following the procedure of Example 9 but substituting for 2,5-dimethyl-3-ethyl-2-hydroxy-6,7-

benzomorphan the corresponding benzomorphans of Table I or their optical isomers, Example 8, 2,3- dimethyI-S-n-butyI-Z-hydroxy-6,7-benzomorphan (Example 4a) or 2,3-dimethyl-5-n-propyl-2'-hydroxy- 6,7-benzomorphan (Example 4b) there is obtained in place of 3-ethyl-5-methyl-2'-hydroxy-6,7- benzomorphan the corresponding norbenzomorphans or their optical isomers of Table I below.

TABLE I 3,5-dimethyl-2'-hydroxy-6,7-benzomorphan 5-methyl-3-n-propyl-2-hydroxy-6,7-benzomorphan S-methyl-B-i-propyl-Z-hydroxy-6,7-benzomorphan 5-methy1-3-n-butyl-2-hydroxy-6,7-berizomorphan 5-methyl-3-i-butyl-2-hydroxy-6,7-benzomorphan 3-methyl-5-ethyl-2'-hydroxy-6,7-benzornorphan 3-methyl-5-n-propyl-2'-hydroxy-6,7-benzomorphan 3-methyl-5-n-butyl-2-hydroxy-6,7-benzomorphan 3-methyl-5-pentyl-2-hydroxy6,7-benzomorphan 3,5-diethyl-2'-hydroxy-6,7-benzomorphan 3-ethyl--n-butyl-2-hydroxy-6,7-benzomorphan 3-ethyl-5-n-propyl-2'-hydroxy-6,7-benzomorphan 3,5-dipropyl-2-hydroxy-6,7-benzomorphan- 5-methyl-3-benzyl-2' -hydroxy-6,7-benzomorphan E-me thyl-3-phenethyl-2'-hydroxy-6,7- benzomorphan S-methyLS-phenyI-Z'-hydroxy-6,7-benzomorphan 5-methyl-3-phenyl-2'-hydroxy-6,7-benzomorphan f fiiliil nl f 'ZhYEEK H E EBPKBQE L' EXAMPLE 1 l m.), cyclopropylcarbonyl chloride (1.67 g., 0.016 m.),

triethylamine (1.62 g., 0.016 m.), and 65 ml. methylene chloride and stirred under reflux for hours. Thesolvent is evaporated and the residue taken up in 250 ml. of ether and washed with 5 percent aqueous hydrochloric acid, water, 5 percent aqueous sodium bicarbonate, and water (50 ml. of each). The organic solution is dried over magnesium sulfate, filtered and evaporated. The residue, dissolved in 50 ml. of ether, is added dropwise to a stirred slurry of 1.5 g. of lithium aluminum hydride in 150 ml. of ether and the organic slurry is stirred and heated under reflux for 5 hours, cooled, 3 ml. of water is then added dropwise and the mixture filtered and the residue thoroughly washed with fresh ether. The combined filtrates are evaporated and the residue dissolved in 25 ml. acetone and the solution filtered. The filtrate is chilled and 510 mg. of product deposits. Recrystallization from methanol-acetone (1:1) gives 380 mg., mp. 189-192 C.

EXAMPLE 12 When the procedure of Example 11 is followed but substituting for cyclopropylcarbonyl chloride each of the acid chlorides of Table 1 below, there is obtained each of the corresponding 2-substituted-3-ethyl-5- methyl-2-hydroxy-6,7-benzomorphans listed in Table II below.

TABLE I TABLE II 2,3-diethyl-S-methyl-2'-hydroxy-6,7-benzomorphan 2-propyl-3-ethyl-5 methyl-2'-hydroxy-6,7-

benzomorphan 2-(3-butenyl)-3-ethyl-5-methyl-2'-hydroxy-6,7-

benzomorphan 2-( Z-methally)-3-ethyl-5-methyl-2-hydroxy-6,7-

benzomorphan 2-( 4-pentenyl)-3-ethyl-5-methyl-2'-hydroxy-6,7-

benzomorphan 2-cyclobutylmentyl-3-ethyl-5 methyl-2-hydroxy u 6,7-beniomorp han 7 Z-cyclopropylethyl-3-ethyl-5-methyl-2-hydroxy-6,7-

benzomorphan 2-(3-cyclopentenylmethyl)-3-ethyl-5-methyl-2'- hydroxy-6,7-benzomorphan 2-( l-cyclobutenylethyl)-3-ethyl-5-methyl-2-hydroxy-6,7-benzomorphan 2-(2-methylcyclopropylmethyl-3-ethyl-5-methyl-2'- hydroxy-6,7-benzomorphan 2-(Z-methylenecyclopropylmethyl)-3-ethyl-5- methyl-2'-hydroxy-6,7-benzomorphan 2-(3-vinylcyclopentylmethyl)-3-3-ethyl-5-methyl-2- hydroxy-6,7-benzomorphan 2-(2,2,S-trimethylcyclopropenylmethyl)-3-ethyl-5- methyl-2-hydroxy-6,7-benzomorphan 2-(Z-methylcyclopentenylmethyl)-3-ethyl-5-methyl- 2-hydroxy-6,7-benzomorphan 2-spiropentylmethyl-3-ethyl-5-methyl-2'-hydroxy- 6,7 benzomorphan 2-[spiro(3,2)-5-hexylmethyl-3]-ethyl-5-methyl-2'- hydroxy-.6,7-benzomorphan EXAMPLE 13 When the procedure of Example 11 is followed but substituting for cyclopropylcarbonyl chloride each of the acid chlorides of Table LExample 12, and substituting 3-methyl-5-n-propyl-2'-hydroxy-6,7- benzomorphan or its optical isomers in place of 3- ethyl-5-methyl-2-hydroxy6,7-benzomorphan, then the corresponding 2-substituted-3-methyl-5-n-propyl-2'- hydroxy-6,7-benzomorphans or each of their optical isomers of Table 1 below are synthesized.

TABLE I 2-ethyl-3-rnethyl-5-n-propyl-2-hydroxy-6,7-

' benzomorphan 2-propyl-3-methyl-5-n-propyl-2'-hydroxy-6,7-

benzomorphan 1 2-( S-butenyl)-3-methyl-S-n-propyl-2-hydroxy-6,7-

benzomorphan 2-( Z-methallyl)-3-methyl-5-n-propyl-2'-hydroxy- 6,7-benzomorphan 2-( 4-pentenyl)-3-methyl-5-propyl-2'-hydroxy-6,7-

benzomorphan 2-cyclobutylmethyl-3methyl-5-n-propyl-2'-hydrox- -3-methyl-5-n-propyl-2'-hydroxy-6,7- benzomorphan EXAMPLE 13a When 3-methyl-5-n-butyl-2'-hydroxy-6,7- benzomorphan or its optical isomers is used above in place of 3-methyl-5-n-propyl-2'-hydroxy-6,7- benzomorphan, the corresponding 2-substituted-3- methyl--n-butyl-2-hydroxy-6,7-benzomorphan product is obtained.

EXAMPLE 14 When the procedure of Example 11 is followed but substituting for cyclopropylcarbonyl chloride each of the acid chlorides of Table l, Example 12, with each of the nor-3,5-disubstituted-2'-hydroxy-6,7- benzomorphans or their optical isomers of Table l, Example 10, in place of nor-3-ethyl-5-methyl-2'-hydroxy- 6,7-benzomorphan, then the corresponding 2,3,5- trisubstituted-2-hydroxy-6,7-benzo-morphans or their optical isomers are formed. Some of these are in Table I below.

TABLE I 2-methylencyclopropylmethyl-3-n-propyl-5-meth yl- 2'-hydroxy-6,7-benzomorphan 2-methylenecyclopropylmethyl-3-methyl-5-ethyl-2 hydroxy-6 ,7-benzomorphan 2-methylenecyclopropylmethyl-3,5-diethyl-2 hydroxy-6 ,7-benzomorphan 2-methylenecyclopropylmethyl-3-phenethyl-5- methyl-2 -hydroxy-6,7-benzomorphan 2-methylenecyclopropylmethyl-3-phenyl-S-methyl- 2'-hydroxy-6,7-benzomorphan 2-methylenecyclopropylmethyl-3-n-propyl-5- methyl-2-hydroxy-6,7-benzomorphan 2-methylenecyclopropylmethyl-3-i-propyl-5-methyl- 2-hydroxy-6,7-benzomorphan 2-methylenecyclopropylmethyl-3-n-butyl-5-methyl- 2'-hydroxy-6,7-benzomorphan 2-methylenecyclopropylmethyl-3-i-butyl-5-methyl- 2-hydroxy-6,7-benzomorphan 2-methylenecylopropylmethyl-3,5-dipropyl-2- hydroxy6,7-benzomorphan 2-methylenecyclopropylmethyl-3-benzyl-S-methyl- 2'-hydroxy-6,7-benzomorphan 2-methylenecyclopropylmethyl-3-methyl-5-phenyl- 2' -hydroxye6,7-benzomorphan 2-methylenecyclopropylmethyl-3,5-diphenyl-2 hydroxy-6,7-benzomorphan 2-methylenecyclopropylmethyl-3-methyl-5-( phydroxy-phenyl )-2-hydroxy-6,7-benzomorphan 2-ethyl-3,5-diethyl-2'-hydroxy-6 ,7-benzomorphan 2-( 3-butenyl )-3,5-diethyl-2'-hydroxy-6,7-

benzomorphan 2-( 4-pentenyl )-3,5-diethyl-2-hydroxy-6,7-

benzomorphan 2-( 2-methylenecyclopropylmethyl )-3,5-diethyl-2- hydroxy-6.7-benzomorphan 2-( 2-methylencyclopropylmethyl )-3-phenethyl-5- methyl-2'-hydroxy-6,7-benomorphan 2-( 3-cyclopentenylmethyl )-3,5-diethyl-2'-hydroxy- 6,7-benzomorpl'1an 2-( 3-butenyl )-3-phenyl-5-methyl-2-hydroxy-6,7-

benzomorphan 2-cyclopropylmethyl-3-methyl-5-pentyl-2-hydroxy- 6,7-benzomorphan 2 ,S-di-n-propyl-3-methyl-2 -hydroxy-6,7-

benzomorphan 2-( 2-methallyl )-3-benzyl-5-methyl-2'-hydroxy-6,7-

benzomorphan 2-(2-cyclobutylmethyl)-3,5-diphenyl-2-hydroxy- 6,7-benzomorphan 2-( 2-methylcyclopropylmethyl )-3-methyl-5-phenyl- 2' -hydroxy-6,7-benzomorphan 2-( 2-methylcyclopentenylmethyl )-3,5-dipropyl-2'- hydroxy-6,7-benzomorphan 2-(spiropentylmethyl)-3,5-diethyl-2-hydroxy-6,7-

benzomorphan EXAMPLE l5 2-Methylenecyclopropylmethyl-3,5-dimethyl-2'- hydroxy-6,7-benzomorphan A solution of 2.0 g. 3,5-dimethyl-2-hydroxy-6,7- benzomorphan, 2.4 g. methylenecyclopropane carboxylic acid chloride and 2.4 g. triethylamine in ml. methylene chloride is stirred and heated under reflux for 8 hours. The reaction mixture is diluted with 250 ml. of ether and washed with 5 percent aqueous hydrochloric acid (100 ml.), water (100 ml. 5 percent aqueous ammonia (100 ml.) and water (100 ml.). The organic solution is dried over magnesium sulfate, filtered and concentrated to dryness and the residue taken up in 50 ml. of ether. The ether solution is added dropwise ta stirred slurry of 1.1 g. lithium aluminum hydride in 250 ml. of ether. After stirring and heating under reflux for 6 hours, 2.2 ml. of water is added dropwise and the inorganic salts are separated by suction filtration and then thoroughly washed with fresh ether. The combined filtrates are concentrated to 100 ml. and extracted twice with 25 ml. of a mixture of 7 ml. concentrated hydrochloric acid dissolved in 143 ml. of water. The combined extracts are made basic with concentrated ammonia and ether extracted (3 X 100 ml.). The ether extracts are then dried over magnesium sulfate, filtered and evaporated and the residue is dissolved in 5 ml. of methanol and treated with 2 ml, of 48 percent ethanolic hydrochloric acid. This solution is evaporated to dryness and the residue triturated with ether to yield 1.6 grams of product. This is dissolved in 10 ml. of hot isopropanol and then 25 ml. of ethyl acetate added. On cooling 1.2 grams of crystalline A compound of the formula:

HO CH 

